Does metformin reduce the risk of cancer in obesity and diabetes? A systematic review and meta-analysis.

AIM: To evaluate the effect of metformin on cancer incidence in subjects with overweight/obesity and/or prediabetes/diabetes. MATERIALS AND METHODS: We searched MEDLINE, Embase and CENTRAL for randomized controlled trials (RCTs) in adults with overweight/obesity and/or prediabetes/diabetes that compared metformin to other interventions for ≥24 weeks. Independent reviewers selected and extracted data including population and intervention characteristics and new diagnoses of cancer. We used the RoB 2.0 risk-of-bias tool and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework to assess risk of bias and certainty of evidence. RESULTS: From 14 895 records after removal of duplicates, 27 trials were included, providing a total of 10 717 subjects in the metformin group and 10 003 in the control group, with 170 and 208 new cases of cancer, respectively. Using a random-effects model, the relative risk was 1.07 (95% confidence interval 0.87-1.31), with similar results in subgroup analyses by study duration or effect of control intervention on weight. Risk of bias in most studies was low, and no evidence of publication bias was found. Trial sequential analysis provided evidence that the cumulative sample size was large enough to exclude a significant effect of metformin on cancer incidence. CONCLUSIONS: Metformin did not reduce cancer incidence in RCTs involving subjects with overweight/obesity and/or prediabetes/diabetes.

Obesity, diabetes, and cancer: epidemiology, pathophysiology, and potential interventions.

The proportion of deaths attributable to cancer is rising, and malignant neoplasms have become the leading cause of death in high-income countries. Obesity and diabetes are now recognized as risk factors for several types of malignancies, especially endometrial, colorectal, and postmenopausal breast cancers. Mechanisms implicated include disturbances in lipid-derived hormone secretion, sex steroids biosynthesis, hyperinsulinemia, and chronic inflammation. Intentional weight loss is associated with a mitigation of risk for obesity-related cancers, a phenomenon observed specially with bariatric surgery. The impact of pharmacological interventions for obesity and diabetes is not uniform: while metformin seems to protect against cancer, other agents such as lorcaserin may increase the risk of malignancies. However, these interpretations must be carefully considered, since most data stem from bias-prone observational studies, and high-quality randomized controlled trials with appropriate sample size and duration are needed to achieve definite conclusions. In this review, we outline epidemiological and pathophysiological aspects of the relationship between obesity, diabetes, and malignancies. We also highlight pieces of evidence regarding treatment effects on cancer incidence in these populations.

Evaluation of UGT1A1 and CYP3A Genotyping and Single-Point Irinotecan and Metabolite Concentrations as Predictors of the Occurrence of Adverse Events in Cancer Treatment.

PURPOSE: The variability on irinotecan (IRI) pharmacokinetics and toxicity has been attributed mostly to genetic variations in the UGT1A1 gene, responsible for conjugation of the active metabolite SN-38. Also, CYP3A mediates the formation of inactive oxidative metabolites of IRI. The association between the occurrence of severe adverse events, pharmacokinetics parameters, and UGT1A1 and CYP3A4 predicted phenotypes was evaluated, as the evaluation of [SN-38]/IRI dose ratio as predictor of severe adverse events. METHODS: Forty-one patients undergoing IRI therapy were enrolled in the study. Blood samples were collected 15 min after the end of drug the infusion, for IRI, SN-38, SN-38G, bilirubin concentrations measurements, and UGT1A1 and CYP3A genotype estimation. Data on adverse event was reported. RESULTS: Fifteen patients (36.5%) developed grade 3/4 adverse events. A total of 9.8% (n = 4) of the patients had UGT1A1 reduced activity phenotype, and 48.7% (n = 20) had UGT1A1 and 63.4% (n = 26) CYP3A intermediary phenotypes. Severe neutropenia and diarrhea were more prevalent in patients with reduced UGT1A1 in comparison with functional metabolism (50% and 75% versus 0% and 13%, respectively). SN-38 levels and its concentrations adjusted by IRI dose were significantly correlated to toxicity (rs = 0.31 (p = 0.05) and rs = 0.425 (p < 0.01)). The [SN-38]/IRI dose ratio had a ROC curve of 0.823 (95% CI 0.69-0.956) to detect any severe adverse event and 0.833 (95% CI 0.694-0.973) to detect severe diarrhea. The cut-off of 0.075 ng mL-1 mg-1 had 100% sensitivity and 65.7% specificity to predict severe diarrhea. CONCLUSION: Our data confirmed the relevance of the pre-emptive genotypic information of UGT1A1. The [SN-38]/IRI ratio, measured 15 min after the end of the IRI infusion, was a strong predictor of severe toxicity and could be applied to minimize the burden of patients after IRI administration.

Obesity, diabetes, and cancer: epidemiology, pathophysiology, and potential interventions

ABSTRACT The proportion of deaths attributable to cancer is rising, and malignant neoplasms have become the leading cause of death in high-income countries. Obesity and diabetes are now recognized as risk factors for several types of malignancies, especially endometrial, colorectal, and postmenopausal breast cancers. Mechanisms implicated include disturbances in lipid-derived hormone secretion, sex steroids biosynthesis, hyperinsulinemia, and chronic inflammation. Intentional weight loss is associated with a mitigation of risk for obesity-related cancers, a phenomenon observed specially with bariatric surgery. The impact of pharmacological interventions for obesity and diabetes is not uniform: while metformin seems to protect against cancer, other agents such as lorcaserin may increase the risk of malignancies. However, these interpretations must be carefully considered, since most data stem from bias-prone observational studies, and high-quality randomized controlled trials with appropriate sample size and duration are needed to achieve definite conclusions. In this review, we outline epidemiological and pathophysiological aspects of the relationship between obesity, diabetes, and malignancies. We also highlight pieces of evidence regarding treatment effects on cancer incidence in these populations.

Outcomes and Prognostic Factors of Patients with Metastatic Colorectal Cancer Who Underwent Pulmonary Metastasectomy with Curative Intent: A Brazilian Experience.

BACKGROUND: We aimed to identify clinicopathological and molecular features associated with progression-free survival (PFS) and overall survival (OS) after pulmonary metastasectomy for metastatic colorectal cancer in a retrospective cohort in Brazil. MATERIALS AND METHODS: We did a retrospective review of thoracic surgeries performed in a single large academic hospital in Brazil from January 1985 to September 2019. Demographics, previously described prognostic factors, and clinicopathological and molecular characteristics were abstracted. Univariate Cox regression was performed for each variable, and, when significant, data were dichotomized to provide clinically meaningful thresholds. RESULTS: Records from 698 patients were reviewed. Fifty-eight patients underwent pulmonary metastasectomy with curative intent. Of those, 53.4% had a single metastatic lesion. The median size of the largest lesion was 1.5 cm. Results of RAS, RAF, and mismatch repair testing and of cytokeratin 20 (CK20) and CDX2 testing were available for 13.8% and 58.6% of the sample, respectively. Median PFS was 14 months, median OS was 58 months, and 5-year survival was 49.8%. Unfavorable prognostic factors for OS included disease-free interval (DFI) <24 months, synchronous presentation, size of the largest lesion ≥2 cm, and loss of CK20 expression. Presenting with more than one lesion was prognostic for PFS but not for OS. CONCLUSION: In this Brazilian cohort, our findings corroborate existing data supporting DFI, synchronous presentation, and number and size of lesions as prognostic factors. Furthermore, we found that loss of CK20 expression may be associated with more aggressive disease and shorter OS. Additional molecular prognostic factors after pulmonary metastasectomy for colorectal cancer should be further explored. IMPLICATIONS FOR PRACTICE: This study consolidates disease-free interval, synchronous presentation, and number and size of lesions as clinically relevant data that may help guide therapy for patients with colorectal cancer and lung metastases who are candidates for curative-intent metastasectomy. Additionally, in this sample, lack of cytokeratin 20 expression in metastases was associated with shorter progression-free survival and overall survival, suggesting that biomarkers also may have a role in guiding therapy in this setting and that additional biomarkers should be further explored.

Evaluation of dried blood spots as an alternative matrix for therapeutic drug monitoring of abiraterone and delta(4)-abiraterone in prostate cancer patients.

Therapeutic drug monitoring (TDM) approaches may benefit patients treated with abiraterone acetate (AA) as drug efficacy is imprecise and important pharmacokinetic variability is known. Current methods based on the analysis of plasma present the disadvantage of the fast degradation of the analytes in the liquid sample. Dried blood spots (DBS) consist of a minimally invasive and unexplored sampling strategy to monitor the levels of abiraterone (ABI) and delta(4)-abiraterone (D4A) in patients. This study presents the development and validation of a precise and accurate method to monitor ABI and D4A in DBS samples by UPLC-MS/MS. Bioanalytical method validation was carried out according to current guidelines, evaluating the impact of DBS-specific parameters such as hematocrit and spot volume on accuracy. Based on the analysis of quality control samples prepared at low, medium and high concentrations, the method was precise with CV ≤ 6.97 % and 10.26 % for ABI and D4A, respectively. The method was also highly accurate, between 93.6-106.8 % for ABI and 96.0-108.5 % for D4A. The DBS method is compatible with the analysis of samples of unknown volume and hematocrit range of the studied population. In addition, ABI and D4A were stable for 7 days in DBS at room temperature, which is feasible for sample transportation in postal service and analysis in the laboratory. Method application to 16 clinical samples revealed good correlation between measured plasma concentrations and estimated plasma concentrations for ABI (r = 0.884, P < 0.05) and D4A (r = 0.920, P < 0.05). Passing-Bablok regression analysis and Bland-Altmann plots indicated correlation between the results obtained from DBS and plasma, with a slight overestimation of the concentrations of ABI in DBS, which could be related to the small study cohort. Therefore, the results of this first work indicate that DBS consist of a promising alternative sampling strategy in TDM studies of AA.

Resistance to differentiation affects ribo- and deoxyribonucleotide pools and sensitivity to pyrimidine metabolism antagonists in HL60 cells.

HL60 myeloid leukemia cells are extensively used as a differentiation model. We investigated a variant of HL60 which is resistant to differentiation induction (HL60-R) by standard differentiation inducers such as retinoic acid and dimethylsulfoxide (DMSO). To find an explanation for this resistance, we examined nucleotide (NTP) and deoxynucleotide (dNTP) pools in HL60-R and its parent cell line, sensitive to differentiation, HL60-S. We also explored whether these differences led to a difference in sensitivity to various antimetabolites. Drug sensitivity was measured with the tetrazolium (MTT) assay, while nucleotides were measured with anion-exchange HPLC. HL60-R cells were between 2- and 5-fold resistant to the antimetabolites 5-fluorouracil, Brequinar, hydroxyurea and N-(phosphonacetyl)-L-aspartate (PALA), but more sensitive to aza-2'-deoxycytidine (DAC), cytarabine and thymidine (5- to 10-fold). The NTP pools in both HL60 variants showed a normal pattern with ATP being the highest (2530-2876 pmol/106 cells) and CTP being lowest. However, UTP pools were 2-fold higher in the HL60-S cells (p < .01), while CTP and GTP pools were 30% higher (p < .01) compared to HL60-R cells. For the dNTP pools, larger differences were observed, with dATP (50 pmol/106 cells) being highest in HL60-R cells, but dATP was 4-fold lower in HL60-S cells. In HL-60-R, the triple combination retinoic acid, DMSO and DAC increased all NTPs almost 2-fold in contrast to HL60-S. Uridine increased UTP (1.4-fold), CTP (2-fold) and dCTP (1.4.-fold) pools in both cell lines, but thymidine increased only dTTP pools (4- to 7-fold), with a depletion of dCTP. PALA decreased UTP and CTP in both cell lines, but increased ATP (only in HL60-R). Hydroxyurea decreased dNTP especially in HL60-S cells. In conclusion, the pronounced differences in NTP and dNTP pools between HL60-S and HL60-R possibly play a role in the induction of differentiation and drug sensitivity.

A quick UPLC-MS/MS method for therapeutic drug monitoring of abiraterone and delta(4)-abiraterone in human plasma.

Abiraterone acetate efficacy against prostate cancer is dependent on the circulating levels of abiraterone and its active metabolites, which present significant pharmacokinetic variability among patients. Thus, therapeutic drug monitoring can be performed to improve treatment outcomes. To support such studies, there are only a limited number of bioanalytical methods in current literature. This work presents a fast method to quantify abiraterone and D4A in plasma in 4 min by UPLC-MS/MS. Bioanalytical method validation was performed according to the recommendations of the US Food and Drug Administration. The method was linear within the range of 1-400 ng/ml for abiraterone and 0.2-20 ng/ml for D4A (r2 > 0.99). Based on the analysis of quality control samples at the lower limit of quantification, low, medium and high concentrations, the method was precise (CVabiraterone ≤ 9.72%; CVD4A ≤ 14.64%) and accurate (CVabiraterone 95.51-107.59%; CVD4A 98.04-99.89%). Application of the method to the quantification of abiraterone and D4A in 10 clinical samples revealed important variability in the conversion ratio of abiraterone to D4A (CV 90.85%). Considering the current literature, this is the fastest method to quantify abiraterone and D4A in plasma, allowing for optimization of the analytical routine.

Health-related quality of life before and during chemotherapy in patients with early-stage breast cancer.

OBJECTIVES: Identify the main changes in the health-related quality of life (HRQoL) of women diagnosed with breast cancer (BC) undergoing chemotherapy. METHODS: Prospective cohort study that included 33 women diagnosed with clinical stages I-III BC and who underwent adjuvant chemotherapy. HRQoL was assessed using the EORTC QLQ-C30 and EORTC QLQ-BR23 instruments 1 week before the start of chemotherapy and during the third month of chemotherapy. RESULTS: There was a decline in the HRQoL scores of patients during treatment. Therefore, chemotherapy alters the patient's perceptions of their HRQoL since there is a decrease in global health status/quality of life (QoL) and functional scales such as physical functioning, role functioning, emotional functioning, social functioning, body image, sexual function and sexual enjoyment. We also observed an increase in side effects related to the systemic therapy, fatigue, nausea and vomiting, insomnia, appetite loss and diarrhoea, despite a decrease in breast symptoms and arm symptoms. CONCLUSIONS: HRQoL was negatively affected during chemotherapy. Even though HRQoL assessment is a useful method for optimising patients' care, its implementation into clinical practice remains a challenge. Since side effects are very often underestimated, we consider that the evaluation of HRQoL parameters should be done for BC patients treated with chemotherapy.

Qualidade de Vida Relacionada à Saúde de Pacientes com Câncer de Mama: Revisão Integrativa da Literatura / Health-Related Quality of Life of Breast Cancer Patients: Integrative Literature Review / Calidad de Vida Relacionada con la Salud de Pacientes con Cáncer de Mama: Revisión Integradora de la Literatura

Introdução: O câncer de mama pode alterar a qualidade de vida relacionada à saúde das pacientes. Objetivo: Compreender o impacto da quimioterapia para câncer de mama na qualidade de vida relacionada à saúde de pacientes. Método: Trata-se de uma revisão integrativa da literatura, compreendendo artigos publicados entre 2007 e 2019, disponíveis nas bases de dados PubMed, LILACS e SciELO. Analisaram-se 25 artigos na íntegra. Resultados: Os questionários mais frequentemente utilizados nos estudos foram o European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) e o módulo complementar European Organization for Research and Treatment of Cancer Breast Cancer-specific Quality of Life Questionnaire (EORTC QLQ-BR23). Em relação às alterações da qualidade de vida, a saúde global diminui durante a quimioterapia, mas pode melhorar após o término do tratamento. O aumento dos sintomas é relatado em diversos estudos e prejudicou a qualidade de vida relacionada à saúde das pacientes. Entretanto, os sintomas diminuem após o término da quimioterapia, exceto para algumas escalas. As escalas de imagem corporal, função sexual e funcionamento físico pioram ao longo do tratamento. A qualidade de vida mental/psicológica tem oscilações durante o tratamento, assim como a escala sobre as relações sociais. Conclusão: A qualidade de vida relacionada à saúde de mulheres com câncer de mama é afetada negativamente pelo tratamento quimioterápico, expressando maior impacto nas escalas de sintomas.

Introduction: Breast cancer can change the health-related quality of life of patients. Objective: To understand the impact of chemotherapy for breast cancer on the health-related quality of life of patients. Method:Integrative review of the literature, comprising articles published between 2007 and 2019, available in PubMed, LILACS and SciELO databases. It were analyzed 25 articles. Results: The questionnaires most frequently used in the studies were the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and the European Organization for Research and Treatment of Cancer Breast Cancer-specific Quality of Life Questionnaire (EORTC QLQ-BR23) complementary module. In relation to changes in the quality of life, the global health diminishes during chemotherapy, but may improve after the end of the treatment. The increase of the symptoms is reported in several studies and have impaired the patients' health-related quality of life. However, symptoms decrease after chemotherapy ends, except in some scales. Body image, sexual function and physical functioning scales get worse throughout the treatment. Mental/psychological quality of life has oscillations during treatment, as does the scale on social relationships. Conclusion: The health-related quality of life of women with breast cancer is negatively affected by chemotherapy treatment, causing major impact in the scales of symptoms.

Introducción: El cáncer de mama puede alterar la calidad de vida relacionada con la salud de las pacientes. Objetivo: Comprender el impacto de la quimioterapia para el cáncer de mama en la calidad de vida relacionado con la salud de los pacientes. Método: Es una revisión integradora de la literatura, que comprende artículos publicados entre 2007 y 2019, disponibles en las bases de datos PubMed, LILACS y SciELO. Se analizaron 25 artículos en su totalidad. Resultados: Los cuestionarios más utilizados fueron European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) y European Organization for Research and Treatment of Cancer Breast Cancer-specific Quality of Life Questionnaire (EORTC QLQ-BR23). Con respecto a los cambios en la calidad de vida, la salud general disminuye durante la quimioterapia, pero puede mejorar después del final del tratamiento. El aumento de los síntomas se informa en varios estudios y afecta la calidad de vida relacionado con la salud de los pacientes. Sin embargo, los síntomas disminuyen después de que termina la quimioterapia, excepto en algunas escalas. Las escalas de imagen corporal, la función sexual y la función física empeoran a lo largo del tratamiento. La calidad de vida mental/psicológica tiene oscilaciones durante el tratamiento, al igual que la escala en las relaciones sociales. Conclusión: La calidad de vida relacionada con la salud de las mujeres con cáncer de mama se ve afectada negativamente por el tratamiento quimioterapéutico, que expresa un mayor impacto en las escalas de los síntomas.

Differences in Breast Cancer Stage at Diagnosis by Ethnicity, Insurance Status, and Family Income in Young Women in the USA.

PURPOSE: Describe the clinical and epidemiological data from young women with breast cancer and determine the association between ethnicity, insurance status, family income, and breast cancer stage at the diagnosis in this population. METHODS: Women under the age of 40 diagnosed with invasive breast cancer from 2010 to 2014 and identified in the Surveillance, Epidemiology, and End Results (SEER) 18 registries database were included. Binary logistic regression was applied in order to estimate the odds ratios (ORs) for factors that were potentially predictive for receiving a breast cancer diagnosis at stage I. RESULTS: Of 14,379 young women with invasive breast cancer, 70.9% of the patients were white, 15.9% black, and 13.2% classified as other ethnicity (American Indian, Asian, Pacific Islander). The initial clinical stage at diagnosis was stage I in 28.2%, II in 45.2%, III in 19.0%, and IV in 7.6%. The chi-square test showed a significant association between clinical stage at diagnosis and family income (p < 0.0001), insurance status (p < 0.0001), and ethnicity (p < 0.0001). The ORs for being diagnosed at stage I, regarding different factors, revealed that women with family income higher than US$ 85,000 were more likely to be diagnosed with stage I (OR [95%CI], 1.306 [1.173-1.454]; p value < 0.0001) when compared with patients with family income of less than US$ 60,000. Black women were less likely to be diagnosed with stage I (OR [95%CI], 0.676 [0.605-0.755]; p value < 0.0001), when compared with white women. Uninsured women were less likely to be diagnosed with stage I (OR [95%CI], 0.586 [0.529-0.648]; p value < 0.0001) when compared with women with insurance coverage. CONCLUSION: Among young US women diagnosed with invasive breast cancer, most of them presented early stage disease. Women with black ethnicity, low income, and uninsured are at risk for late-stage presentation. Improvements in strategies to allow earlier breast cancer diagnosis in these at risk population are urged.

Tropomyosin-Related Kinase Receptor and Neurotrophin Expression in Cutaneous Melanoma Is Associated with a Poor Prognosis and Decreased Survival.

OBJECTIVE: Normally, activation of tropomyosin-related kinase (TRK) receptors by neurotrophins (NTs) stimulates intracellular pathways involved in cell survival and proliferation. Dysregulation of NT/TRK signaling may affect neoplasm prognosis. Data on NT and TRK expression in melanomas are limited, and it is unclear whether NT/TRK signaling pathways are involved in the origin and progression of this neoplasm. METHODS: We examined whether NT/TRK expression differs across different cutaneous melanoma grades and subtypes, and whether it is associated with melanoma prognosis and survival. A cross-sectional study was performed in which the expression of TrkA, TrkB, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) was analyzed by immunohistochemistry of 154 melanoma samples. We investigated NT/TRK expression associations with prognostic factors for melanoma, relapse-free survival (RFS), and overall survival (OS). RESULTS: Of the 154 melanoma samples, 77 (55.4%) were TrkA immunopositive, 81 (58.3%) were TrkB immunopositive, 113 (81.3%) were BDNF immunopositive, and 104 (75.4%) were NGF immunopositive. We found NT/TRK expression associated strongly with several clinical prognostic factors, including the tumor-node-metastasis stage (p < 0.001), histological subtype (p < 0.001), and Clark level (p < 0.05), as well as with a worse OS (p < 0.05 for all, except TrkB) and RFS (p < 0.05 for all). CONCLUSIONS: Our results show strong associations of NT/TRK expression with melanoma stage progression and a poor prognosis.

Combined Inhibition of HDAC and EGFR Reduces Viability and Proliferation and Enhances STAT3 mRNA Expression in Glioblastoma Cells.

Changes in expression of histone deacetylases (HDACs), which epigenetically regulate chromatin structure, and mutations and amplifications of the EGFR gene, which codes for the epidermal growth factor receptor (EGFR), have been reported in glioblastoma (GBM), the most common and malignant type of brain tumor. There are likely interplays between HDACs and EGFR in promoting GBM progression, and HDAC inhibition can cooperate with EGFR blockade in reducing the growth of lung cancer cells. Here, we found that either HDAC or EGFR inhibitors dose-dependently reduced the viability of U87 and A-172 human GBM cells. In U87 cells, the combined inhibition of HDACs and EGFR was more effective than inhibiting either target alone in reducing viability and long-term proliferation. In addition, HDAC or EGFR inhibition, alone or combined, led to G0/G1 cell cycle arrest. The EGFR inhibitor alone or combined with HDAC inhibition increased mRNA expression of the signal transducer and activator of transcription 3 (STAT3), which can act either as an oncogene or a tumor suppressor in GBM. These data provide early evidence that combining HDAC and EGFR inhibition may be an effective strategy to reduce GBM growth, through a mechanism possibly involving STAT3.

Determination of Endogenous Concentrations of Uracil and Dihydrouracil in Dried Saliva Spots by LC-MS/MS: Method Development, Validation, and Clinical Application.

BACKGROUND: The aim of this study was to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the measurement of uracil (U) and dihydrouracil (UH2) concentrations in dried saliva spots (DSSs), for the evaluation of dihydropyrimidine dehydrogenase (DPD) enzyme activity. RESULTS: Nine 18-mm diameter DSS discs were extracted with acetate:isopropyl alcohol (85:15, vol/vol) and analyzed by LC-MS/MS. The assay was linear in the range of 10-1000 ng·mL, with accuracy between 89% and 112% and precision between 5.7% and 13%. The metabolic ratio [UH2]/[U] was stable in DSS for up to 9 days at 45°C. Concentrations of U and UH2, as well as the metabolic ratio, were highly concordant between matrices. Using a metabolic ratio classification cutoff of 1.16 for the identification of slow DPD metabolizers, 98.7% concordance was achieved between SS and saliva. CONCLUSIONS: DSS samples could be a useful alternative for DPD activity screening, particularly in locations with limited access to highly equipped laboratories.

Pharmacokinetic and Pharmacogenetic Markers of Irinotecan Toxicity.

BACKGROUND: Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient's body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment. METHODS: The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data. CONCLUSION: The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of limited sampling and population pharmacokinetic models for IRI doses individualization.

Survival with nal-IRI (liposomal irinotecan) plus 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in per-protocol and non-per-protocol populations of NAPOLI-1: Expanded analysis of a global phase 3 trial.

BACKGROUND: In the phase 3 randomised NAPOLI-1 clinical study, a 45% increase in median overall survival (OS) was shown with liposomal irinotecan, 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) versus 5-FU/LV in patients with metastatic pancreatic cancer progressing after gemcitabine-based therapy. Here, we report data from a pre-specified, expanded analysis of outcomes in the per-protocol (PP) population. MATERIALS AND METHODS: The PP population comprised patients receiving ≥80% of planned treatment during the first 6 weeks, with no major protocol violations. A post-hoc analysis of the non-PP population was also performed. RESULTS: For PP patients, median OS was 8.9 (95% confidence interval: 6.4-10.5) months with nal-IRI+5-FU/LV (n = 66) vs 5.1 (4.0-7.2) months with 5-FU/LV (n = 71; unstratified hazard ratio [HR] 0.57, p = 0.011). For non-PP patients, it was 4.4 (3.3-5.3) months with nal-IRI+5-FU/LV (n = 51) vs 2.8 (1.7-3.2) months with 5-FU/LV (n = 48; unstratified HR 0.64, p = 0.0648). CONCLUSION: A statistically significant survival advantage was observed with nal-IRI+5-FU/LV vs 5-FU/LV in the PP patient population.

DPD functional tests in plasma, fresh saliva and dried saliva samples as predictors of 5-fluorouracil exposure and occurrence of drug-related severe toxicity.

OBJECTIVE: to evaluate plasma and salivary uracil (U) to dihydrouracil (UH2) ratios as tools for predicting 5-fluorouracil systemic exposure and drug-related severe toxicity, and clinically validate the use of dried saliva spots (DSS) as an alternative sampling strategy for dihydropyrimidine dehydrogenase (DPD) deficiency assessment. METHODS: Pre-chemotherapy plasma, fresh saliva and DSS samples were obtained from gastrointestinal patients (N = 40) for measurement of endogenous U and UH2 concentrations by LC-MS/MS. A second plasma sample collected during 5FU infusion was used for 5FU area under the curve (AUC) determination by HPLC-DAD. Data on toxicity was reported according to CTCAE. RESULTS: 15% of the patients developed severe 5FU-related toxicity, with neutropenia accounting for 67% of the cases. U, UH2 and [UH2,]/[U] were highly correlated between fresh and dried saliva samples (rs = 0.960; rs = 0.828; rs = 0.910, respectively). 5FU AUC ranged from 11.3 to 37.31 mg h L-1, with 46.2% of under-dosed and 10.3% over-dosed patients. The [UH2]/[U] ratios in plasma, fresh saliva and dried saliva samples were moderately correlated with 5FU AUC and adverse events grade, indicating a partial contribution of the variables to drug exposure (r = -0.412, rs = -0.373, rs = 0.377) and toxicity (r = -0.363, rs = -0.523, rs = 0.542). Metabolic ratios were lower in patients with severe toxicity (P < .01 salivary ratios, and P < .5 plasma ratios), and 5FU AUC were in average 47% higher in this group than in moderate toxicity. The diagnostic performance of [UH2]/[U] ratios in fresh saliva and DSS for the identification of patients with severe toxicity were comparable. CONCLUSIONS: The [UH2]/[U] metabolic ratios in plasma, fresh saliva and DSS were significantly associated with 5FU systemic exposure and toxicity degree. This study also demonstrated the applicability of DSS as alternative sampling for evaluating DPD activity.

Epidermal Growth Factor Receptor Regulation of Ewing Sarcoma Cell Function.

OBJECTIVE: Ewing sarcoma (ES) is a type of childhood cancer probably arising from stem mesenchymal or neural crest cells. The epidermal growth factor receptor (EGFR) acts as a driver oncogene in many types of solid tumors. However, its involvement in ES remains poorly understood. METHODS: Human SK-ES-1 and RD-ES ES cells were treated with EGF, the EGFR inhibitor tyrphostin (AG1478), or phosphoinositide 3-kinase (PI3K) or extracellular-regulated kinase (ERK)/mitogen-activated kinase (MAPK) inhibitors. Cell proliferation survival, cycle, and senescence were analyzed. The protein content of possible targets of EGFR manipulation was measured by Western blot. RESULTS: Cell proliferation and survival were increased by EGF and inhibited by AG1478. The EGFR inhibitor also altered the cell cycle, inducing arrest in G1 and increasing the sub-G1 population, reduced polyploidy and increased the population of senescent cells. In addition, AG1478 reduced the levels of phosphorylated AKT (p-AKT), ERK, p-ERK, cyclin D1, and brain-derived neurotrophic factor (BDNF), while enhancing p53 levels. Cell proliferation was also impaired by inhibitors of PI3K or ERK, alone or combined with AG1478. CONCLUSIONS: Our findings reveal novel aspects of EGFR regulation of ES cells and provide early evidence for antitumor activities of EGFR inhibitors in ES.